Post-translational modifications orchestrate the intrinsic signaling bias of GPR52

  • Nat Chem Biol. 2025 Mar 14. doi: 10.1038/s41589-025-01864-w.
Bingjie Zhang  1 ,  Wei Ge  1  2 ,  Mengna Ma  1 ,  Shanshan Li  1 ,  Jie Yu  1  2  3 ,  Guang Yang  4 ,  Huilan Wang  4 ,  Jingwen Li  5 ,  Qingrun Li  5 ,  Rong Zeng  5 ,  Boxun Lu  6 ,  Wenqing Shui  7  8
Affiliations
  • 1. iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3. Lingang Laboratory, Shanghai, China.
  • 4. State Key Laboratory of Medical Neurobiology, New Cornerstone Science Laboratory, School of Life Sciences, Fudan University, Shanghai, China.
  • 5. National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China.
  • 6. State Key Laboratory of Medical Neurobiology, New Cornerstone Science Laboratory, School of Life Sciences, Fudan University, Shanghai, China. [email protected].
  • 7. iHuman Institute, ShanghaiTech University, Shanghai, China. [email protected].
  • 8. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
PMID: 40087539 DOI: 10.1038/s41589-025-01864-w
Abstract

Despite recent advances in G-protein-coupled receptor (GPCR) biology, the regulation of GPCR activation, signaling and function by post-translational modifications (PTMs) remains largely unexplored. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G-protein activity that is emerging as a neurotherapeutic target, we discovered its disproportionately low Arrestin recruitment activity. After profiling the N-glycosylation and phosphorylation patterns, we found that these two types of PTMs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive Gs signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses Arrestin recruitment and attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the Huntingtin protein in brain striatal cells. Our study provides new insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR through distinct PTMs in different motifs.

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